Electrophysiologic, pharmacologic and neurochemical techniques will be used to examine the central and peripheral mechanisms involved in bladder pain induced by the administration of irritant agents into the bladder lumen of rats and cats. The long term aim of the study is to identify the chemical signals that are involved in the neural detection, transmission and processing of noxious events in the lower urinary tract. The study will examine the mechanisms underlying the sensitization of bladder nociceptors by chemical mediators of inflammation, the central pathways for processing bladder nociceptive input, the changes in bladder reflex mechanisms induced by bladder pain and the interactions of putative afferent and efferent transmitter systems in the bladder wall. Several hypothesis will be tested: (1) that bladder pain is triggered in part by normally silent (sleeping C-fibers afferents) that are sensitized by chemical mediators released by pain producing substances, (2) that hyperalgesia defined as a painful response to a normally nonpainful stimulus can be induced in the bladder during an inflammatory state. It is noteworthy in this regard that hyperalgesia has been studied previously only in the somatic sensory system, (3) that neurochemical changes in the spinal cord similar to those induced by somatic pain will accompany acute and chronic inflammation in the urinary bladder, (4) that bladder pain will induce a reduction in bladder capacity by changes in the setpoint of the central micturition reflex pathway, and (5) that communication between afferent and efferent pathways in the peripheral nervous system represents a mechanism by which bladder irritation can influence the motility of the bladder. The long term objectives of this research program are to understand the mechanisms by which irritating or tissue-injuring stimuli in the lower urinary tract are detected and processed by the nervous system and in turn modulate lower urinary tract function. The study will utilize a multidisciplinary approach encompassing neurochemistry, electrophysiology, pharmacology and molecular neurobiology.